RUNX2 and cardiovascular disorder: Even though E2 used as a positive control shows the slightly higher effect on the proliferation, differentiation, collagenation, mineralization, DNA content and Runx2 gene expression of osteoblasts than lower doses, however, the side effects of the long-term use of estrogen, such as a higher incidence of endometrial cancer, cardiovascular disease and breast carcinoma, could not be ignored.